Despite recent improvements in cancer therapy due to the introduction of novel therapeutics, the incidence of cancer has been on the rise. Traditional chemotherapy is still one of the pillars for the treatment of cancer. Chemotherapy is often based on the use of drugs that are toxic to cancer cells. Several general classes of chemotherapeutic drugs have been developed. One such class of genotoxic drugs that have been shown to damage cellular DNA by producing crosslinks therein are cisplatin [cis-diamminedichloroplatinum(II)] and carboplatin [diammine(1,1-cyclobutanedicarboxylato)-platinum(II)] (Eur J Cancer 1998; 34:1535-42; Chem Rev. 1999; 2467-98). Cisplatin is one of the most commonly used chemotherapeutic agents, and is a first line therapy for most malignancies. Cisplatin and other Pt(II) analogs, such as carboplatin and oxaliplatin, are currently used in the treatment of selected, diverse neoplasms of epithelial and mesenchymal origin.
However, traditional chemotherapeutic agents are not tumour specific; their selectivity largely relies on the premise that rapidly proliferating cells are more prone to the cytotoxic effect of these drugs. Therefore, increased toxicities against normal tissues characterized by an enhanced proliferation rate represent a major drawback of this approach. As consequence of this low efficacy and unspecific toxicity, chemotherapeutics are often given at suboptimal doses. For example, Cisplatin and related Pt (II) agents are characterised by nephrotoxicity, neurotoxcity and myelosupression. Thus, the unmet medical need is for innovative strategies that focus toxicity to tumor cells while sparing healthy tissues. The development of antibody-drug conjugates (ADCs) by empowering antibodies or a targeting-ligand with a cytotoxic drug directed against tumor-associated antigens represents a promising therapeutic strategy for site-specific drug delivery.
The antibody-drug conjugate (ADCs) concept is a promising strategy to deliver a cytotoxic drug selectively to a target. Such conjugates represent a broadly applicable approach to enhance the antitumor activity of antibodies, and improve the tumor-to-normal tissue selectivity of chemotherapy (Cancer J 2008; 14:154-169). A significant number of ADCs are currently in clinical development, and recently Brentuximab vedotin (SGN-35) has been approved by the FDA (CCR Focus, Clin Can Res 2011:17). Although immuno-conjugates of doxorubicin (Cancer Res. 1992; 15; 5693-700), cisplatin (J Pharm Sci. 1997; 86:1478-83) and taxanes (Cancer Res 2001; 61, 694-699) has been tried before, developing antibody-targeted chemotherapeutics has been a challenge. The major problem associated were loss of structural integrity of antibodies and drug potency. Significant progress in these areas has been made, with careful optimization of several parameters, including antibody specificity, drug potency, linker technology, and the stoichiometry and placement of conjugated drugs (Curr Opin Chem Biol. 2010; 14:529-37).
Site-specific delivery of platinum compounds to tumor cells has been attempted previously. This was achieved by directly complexing platinum to PEG and delivering the drug in the untargeted form or as ligand-targeted conjugate to tumor associated antigens. In one report, attempt was made to conjugate carboplatin with PEG (Polym Adv Technol. 2000; 11:635-41). In other examples of prior art, folate-targeted PEGylated carboplatin analogs (Bioconj Chem. 2003; 14:563-74) as well as peptide-targeted carboplatin were tested on tumor cells in vitro (Bioconj Chem. 2004; 4:814-23). The complexes were ineffective for practical usage in terms of cytotoxicity, antigen binding activity and in vivo stability. The limitations associated to previous versions of Pt-antibody conjugates could be attributed to the use of antibodies of murine origin, the choice of the cell surface receptor, method of synthesis resulting in the potential binding of Pt to the antibody disulfides, or inability of the Pt to aquate due to formation of stable linkages resulting in inefficient release kinetics.